Phase IIa Study of AV411, a Glial Activation Inhibitor, for Opioid Withdrawal (AV411)

• ClinicalTrials.gov Identifier: NCT00723177
• Recruitment Status: Completed
• First Posted: July 28, 2008
• Results First Posted: December 5, 2016
• Last Update Posted: December 5, 2016
• Sponsor: New York State Psychiatric Institute
• Collaborator: National Institute on Drug Abuse (NIDA)
• Information provided by (Responsible Party): New York State Psychiatric Institute

Tracking Information

• First Submitted Date: July 24, 2008
• First Posted Date: July 28, 2008
• Results First Submitted Date: March 23, 2015
• Results First Posted Date: December 5, 2016
• Last Update Posted Date: December 5, 2016
• Study Start Date: October 2008
• Actual Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 11, 2016)

Subjective Opioid Withdrawal Scale Score (SOWS) [ Time Frame: Measured at the end of each two-week maintenance period (i.e., Placebo, Low AV411, High AV411). ]

Measures severity of opioid withdrawal in opioid dependent populations (0-64). Larger values indicate more severe withdrawal.

• Original Primary Outcome Measures (submitted: July 24, 2008): Total Subjective Opioid Withdrawal Scale score [ Time Frame: Twice daily for the duration of the trial ]

Current Secondary Outcome Measures (submitted: October 11, 2016)

The Effects of AV411 on the Analgesic Effects of Oxycodone. [ Time Frame: Measured at the end of each AV411 of the three two-week maintenance periods ]

The McGill Pain Questionnaire (Melzack, 1987) was used to assess pain experience immediately following the immersion of the hand in 4 degree Celsius water. Scores were added across all 15 items to generate a sum score, which ranged between 15 and 60. Larger scores indicate greater pain levels.

• Original Secondary Outcome Measures (submitted: July 24, 2008): Pupil diameter, heart rate, blood pressure, respiratory rate, body temperature, other subjective measures, plasma levels of AV411 [ Time Frame: Various time points throughout trial ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase IIa Study of AV411, a Glial Activation Inhibitor, for Opioid Withdrawal
• Official Title: The Safety, Tolerability and Preliminary Efficacy of AV411, a Glial Activation Inhibitor, in Heroin Abusers Under Conditions of Morphine Maintenance and Withdrawal
• Brief Summary: Repeated use and/or abuse of opioid medications is generally associated with a characteristic withdrawal syndrome that develops after cessation of drug administration. The present study is designed to evaluate the effectiveness of AV411 to alter opioid-induced withdrawal symptoms.
• Detailed Description: Opioid-induced cytokine release and glial activation has been proposed to directly contribute to the affective and physiological aspects of withdrawal. Furthermore, cytokine release following opioid administration has been hypothesized to be a limiting factor in both the duration and magnitude of opioid-induced analgesia. The two primary goals of our study are to assess AV411's ability to 1) reduce the opioid-withdrawal syndrome and 2) increase and prolong the analgesic effects of the mu-opioid agonist, oxycodone. To explore whether AV411 decreases opioid-induced glial cell activation, some participants assigned to the placebo and high dose AV411 groups (n = 6 for each dose condition) will be studied twice with [11C]PK11195, a positron emission tomography (PET) radiotracer used to measure the peripheral benzodiazepine receptor (PBR) in the human brain. The PBR is a receptor located on the mitochondria of the microglia and can be used to examine microglial activation in various brain regions.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Basic Science
• Condition: Opioid-Related Disorders

Intervention

• Drug: AV411
  Low (20 mg), and high dose (40 mg) of AV411 will be administered orally twice a day (BID) for two consecutive weeks
  Other Name: ibudilast
• Drug: Placebo (PCB)
  Placebo drug will be administered orally twice a day (BID) for two consecutive weeks
  Other Name: PCB or 0 mg

Study Arms

• Placebo Comparator: Placebo
  This group will receive placebo drug
  Intervention: Drug: Placebo (PCB)
• Experimental: Low-dose AV411
  This group will receive a low dose of AV411
  Intervention: Drug: AV411
• Experimental: High-dose AV411
  This group will receive a high dose of AV411
  Intervention: Drug: AV411

Publications *

• Cooper ZD, Johnson KW, Pavlicova M, Glass A, Vosburg SK, Sullivan MA, Manubay JM, Martinez DM, Jones JD, Saccone PA, Comer SD. The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers. Addict Biol. 2016 Jul;21(4):895-903. doi: 10.1111/adb.12261. Epub 2015 May 14.
• Jacobsen JH, Watkins LR, Hutchinson MR. Discovery of a novel site of opioid action at the innate immune pattern-recognition receptor TLR4 and its role in addiction. Int Rev Neurobiol. 2014;118:129-63. doi: 10.1016/B978-0-12-801284-0.00006-3. Review.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 24, 2008): 30
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: June 2012
• Actual Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adults between the ages of 21 and 45
• Current dependence on heroin according to (Diagnostic and Statistical Manual) DSM-IV criteria
• Non-treatment seeking

Exclusion Criteria:

• Female participants who are currently pregnant or breastfeeding. Lack of effective birth control 10 days before Study Day 1 (15 days prior to the first PET scan)
• Self-reported use of methadone, buprenorphine, or levo-alpha-acetylmethadol (LAAM) in the past 14 days
• Participants who have a positive history of neurological illness (including epilepsy) or those who have received anti-convulsant therapy during the past 5 years
• Liver disease requiring medication or medical treatment, and/or aspartate or alanine aminotransferase levels greater than 3 times the upper limit of normal
• Gastrointestinal or renal disease that would significantly impair absorption, metabolism or excretion of study drug, or require medication or medical treatment
• Neurological or psychiatric disorders including psychosis, bipolar disorder, organic brain disease, any seizure history or other disorders that require treatment or that could make study compliance difficult
• Positive tuberculosis (PPD) TB skin test along with a clinical history and chest X-ray indicative of active tuberculosis. (Individuals who have a positive PPD test and have a negative chest X-ray, are not symptomatic for tuberculosis, and do not require anti-tuberculosis therapy will be eligible to participate. Participants will be asked if they ever tested positive for tuberculosis. If so, they will not be given a PPD and a chest X-ray and clinical history will be used for evaluation purposes).
• Presence or positive history of severe medical illness or any cardiovascular disease or heart abnormality, such as low hemoglobin (Hb < 13 g/dL in males, Hb < 11 g/dL in females), or BP > 150/90.
• Requirement for any of the following medications (current or within the past 4 weeks): psychotropics (including sedative/hypnotics, antidepressants, neuroleptics), anticonvulsants, antihypertensives, antiarrhythmics, or antiretroviral medications,. Participants on any current psychoactive prescription medications will be excluded.
• Current dependence (by DSM-IV criteria) on methadone, LAAM, or buprenorphine
• Participants for whom detoxification is not "clinically recommended" such as those with a significant history of overdose following detoxification
• Participation in an investigational drug study within the past 3 months
• Hypersensitivity to any of the medications used in this study
• Participants who are positive for HIV or chronic active hepatitis
• Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan, as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists: "Guide to MR procedures and metallic objects" Shellock Frank G., Lippincott Williams & Wilkins Healthcare, Philadelphia, 2001.
• Lifetime exposure to radiation in the workplace, or participation in nuclear medicine procedures, including research protocols, in the past year
• Positive Allen Test indicating lack of collateral blood flow to hand
• History of Reynaud's syndrome

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00723177
• Other Study ID Numbers: #5725; P50DA009236 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Data have been published in a peer-reviewed journal.

• Responsible Party: New York State Psychiatric Institute
• Study Sponsor: New York State Psychiatric Institute
• Collaborators: National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Sandra D Comer, PhD; New York State Psychiatric Institute and Columbia University

• PRS Account: New York State Psychiatric Institute
• Verification Date: October 2016